Knowledge about globin genetics for precision diagnosis of hemoglobinopathies: A case Study

Abstract

More than 1,800 changes in the synthesis and structure of hemoglobin (Hb) are estimated to exist. Many of them can be identified by chromatographic and electrophoretic analyses. However, in some cases, critical interpretation, accompanied by molecular techniques and gene sequencing, is necessary for diagnosis. This case demonstrates how important is understanding the genetics of globin chains to diagnose complex cases of hemoglobinopathies through the report of a newborn with Hb C/Beta0 thalassemia and heterozygous Hb B2 co-inheritance. A sample from the proband (a 25-day-old girl) was received with an FC hemoglobin profile for confirmatory diagnosis, accompanied by samples from her parents. The chromatographic and electrophoretic analysis confirmed the suggested profile. However, the absence of Hb A2 in the mother raised suspicions about the presence of a delta-chain Hb variant. In addition, high Hb A2 levels of the father sample suggested beta-thalassemia. Considering all possible genotypes that lead to the patient’s profile, we conducted molecular analyses that confirmed heterozygosity for Hb C in the proband and mother, as well as the presence of an allele for beta0-thalassemia (CD39) in the father and child. Furthermore, the presence of Hb B2 or A2‘, a delta chain variant, was detected in homozygosity in the mother and heterozygosity in the patient. Subsequently, the diagnosis was confirmed by sequencing the HBB and HBD genes of the proband and mother, respectively. Confirmation of the diagnosis required specific knowledge about the genetics of globins and refined laboratory methodologies to validate the suspicions raised by chromatographic and electrophoretic investigations.